Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection
Identifieur interne : 001183 ( Ncbi/Merge ); précédent : 001182; suivant : 001184Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection
Auteurs : Rudragouda Channappanavar [États-Unis] ; Lu Lu [République populaire de Chine] ; Shuai Xia [République populaire de Chine] ; Lanying Du [États-Unis] ; David K. Meyerholz [États-Unis] ; Stanley Perlman [États-Unis] ; Shibo Jiang [République populaire de Chine, États-Unis]Source :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2015.
Descripteurs français
- KwdFr :
- Administration par voie nasale, Animaux, Antiviraux (administration et posologie), Charge virale, Coronavirus du syndrome respiratoire du Moyen-Orient (), Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie), Humains, Infections à coronavirus (), Lignée cellulaire, Modèles animaux de maladie humaine, Peptides (administration et posologie), Poumon (virologie), Pénétration virale (), Souris de lignée C57BL.
- MESH :
- administration et posologie : Antiviraux, Peptides.
- physiologie : Coronavirus du syndrome respiratoire du Moyen-Orient.
- virologie : Poumon.
- Administration par voie nasale, Animaux, Charge virale, Coronavirus du syndrome respiratoire du Moyen-Orient, Humains, Infections à coronavirus, Lignée cellulaire, Modèles animaux de maladie humaine, Pénétration virale, Souris de lignée C57BL.
English descriptors
- KwdEn :
- Administration, Intranasal, Animals, Antiviral Agents (administration & dosage), Cell Line, Coronavirus Infections (prevention & control), Disease Models, Animal, Humans, Lung (virology), Mice, Inbred C57BL, Middle East Respiratory Syndrome Coronavirus (drug effects), Middle East Respiratory Syndrome Coronavirus (physiology), Peptides (administration & dosage), Viral Load, Virus Internalization (drug effects).
- MESH :
- chemical , administration & dosage : Antiviral Agents, Peptides.
- drug effects : Middle East Respiratory Syndrome Coronavirus, Virus Internalization.
- physiology : Middle East Respiratory Syndrome Coronavirus.
- prevention & control : Coronavirus Infections.
- virology : Lung.
- Administration, Intranasal, Animals, Cell Line, Disease Models, Animal, Humans, Mice, Inbred C57BL, Viral Load.
Abstract
To gain entry into the target cell, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) uses its spike (S) protein S2 subunit to fuse with the plasma or endosomal membrane. Previous work identified a peptide derived from the heptad repeat (HR) 2 domain in S2 subunit, HR2P, which potently blocked MERS-CoV S protein–mediated membrane fusion. Here, we tested an HR2P analogue with improved pharmaceutical property, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo. HR2P-M2 was highly effective in inhibiting MERS-CoV S protein–mediated cell-cell fusion and infection by pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region. It interacted with the HR1 peptide to form stable α-helical complex and blocked six-helix bundle formation between the HR1 and HR2 domains in the viral S protein. Intranasally administered HR2P-M2 effectively protected adenovirus serotype-5–human dipeptidyl peptidase 4–transduced mice from infection by MERS-CoV strains with or without mutations in the HR1 region of S protein, with >1000-fold reduction of viral titers in lung, and the protection was enhanced by combining HR2P-M2 with interferon β. These results indicate that this combination regimen merits further development to prevent MERS in high-risk populations, including healthcare workers and patient family members, and to treat MERS-CoV–infected patients.
Url:
DOI: 10.1093/infdis/jiv325
PubMed: 26164863
PubMed Central: 4655857
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PMC:4655857Le document en format XML
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<front><div type="abstract" xml:lang="en"><title>Abstract</title>
<p>To gain entry into the target cell, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) uses its spike (S) protein S2 subunit to fuse with the plasma or endosomal membrane. Previous work identified a peptide derived from the heptad repeat (HR) 2 domain in S2 subunit, HR2P, which potently blocked MERS-CoV S protein–mediated membrane fusion. Here, we tested an HR2P analogue with improved pharmaceutical property, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo. HR2P-M2 was highly effective in inhibiting MERS-CoV S protein–mediated cell-cell fusion and infection by pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region. It interacted with the HR1 peptide to form stable α-helical complex and blocked six-helix bundle formation between the HR1 and HR2 domains in the viral S protein. Intranasally administered HR2P-M2 effectively protected adenovirus serotype-5–human dipeptidyl peptidase 4–transduced mice from infection by MERS-CoV strains with or without mutations in the HR1 region of S protein, with >1000-fold reduction of viral titers in lung, and the protection was enhanced by combining HR2P-M2 with interferon β. These results indicate that this combination regimen merits further development to prevent MERS in high-risk populations, including healthcare workers and patient family members, and to treat MERS-CoV–infected patients.</p>
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<double pmid="26164863"><pmc><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection</title>
<author><name sortKey="Channappanavar, Rudragouda" sort="Channappanavar, Rudragouda" uniqKey="Channappanavar R" first="Rudragouda" last="Channappanavar">Rudragouda Channappanavar</name>
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<country>États-Unis</country>
<placeName><settlement type="city">Iowa City</settlement>
<region type="state">Iowa</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University</wicri:regionArea>
<wicri:noRegion>Fudan University</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Xia, Shuai" sort="Xia, Shuai" uniqKey="Xia S" first="Shuai" last="Xia">Shuai Xia</name>
<affiliation wicri:level="1"><nlm:aff id="af4">Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University</wicri:regionArea>
<wicri:noRegion>Fudan University</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name>
<affiliation wicri:level="2"><nlm:aff id="af5">Lindsley F. Kimball Research Institute, New York Blood Center, New York</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État de New York</region>
</placeName>
<wicri:cityArea>Lindsley F. Kimball Research Institute, New York Blood Center</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Meyerholz, David K" sort="Meyerholz, David K" uniqKey="Meyerholz D" first="David K." last="Meyerholz">David K. Meyerholz</name>
<affiliation wicri:level="4"><nlm:aff id="af2">Pathology, University of Iowa, Iowa City</nlm:aff>
<orgName type="university">Université de l'Iowa</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Iowa City</settlement>
<region type="state">Iowa</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name>
<affiliation wicri:level="4"><nlm:aff id="af1">Departments of Microbiology, University of Iowa, Iowa City</nlm:aff>
<orgName type="university">Université de l'Iowa</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Iowa City</settlement>
<region type="state">Iowa</region>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="af3">Pediatrics, University of Iowa, Iowa City</nlm:aff>
<orgName type="university">Université de l'Iowa</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Iowa City</settlement>
<region type="state">Iowa</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name>
<affiliation wicri:level="1"><nlm:aff id="af4">Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University</wicri:regionArea>
<wicri:noRegion>Fudan University</wicri:noRegion>
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<affiliation wicri:level="2"><nlm:aff id="af5">Lindsley F. Kimball Research Institute, New York Blood Center, New York</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État de New York</region>
</placeName>
<wicri:cityArea>Lindsley F. Kimball Research Institute, New York Blood Center</wicri:cityArea>
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<idno type="doi">10.1093/infdis/jiv325</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection</title>
<author><name sortKey="Channappanavar, Rudragouda" sort="Channappanavar, Rudragouda" uniqKey="Channappanavar R" first="Rudragouda" last="Channappanavar">Rudragouda Channappanavar</name>
<affiliation wicri:level="4"><nlm:aff id="af1">Departments of Microbiology, University of Iowa, Iowa City</nlm:aff>
<orgName type="university">Université de l'Iowa</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Iowa City</settlement>
<region type="state">Iowa</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name>
<affiliation wicri:level="1"><nlm:aff id="af4">Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University</wicri:regionArea>
<wicri:noRegion>Fudan University</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Xia, Shuai" sort="Xia, Shuai" uniqKey="Xia S" first="Shuai" last="Xia">Shuai Xia</name>
<affiliation wicri:level="1"><nlm:aff id="af4">Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University</wicri:regionArea>
<wicri:noRegion>Fudan University</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name>
<affiliation wicri:level="2"><nlm:aff id="af5">Lindsley F. Kimball Research Institute, New York Blood Center, New York</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État de New York</region>
</placeName>
<wicri:cityArea>Lindsley F. Kimball Research Institute, New York Blood Center</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Meyerholz, David K" sort="Meyerholz, David K" uniqKey="Meyerholz D" first="David K." last="Meyerholz">David K. Meyerholz</name>
<affiliation wicri:level="4"><nlm:aff id="af2">Pathology, University of Iowa, Iowa City</nlm:aff>
<orgName type="university">Université de l'Iowa</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Iowa City</settlement>
<region type="state">Iowa</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name>
<affiliation wicri:level="4"><nlm:aff id="af1">Departments of Microbiology, University of Iowa, Iowa City</nlm:aff>
<orgName type="university">Université de l'Iowa</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Iowa City</settlement>
<region type="state">Iowa</region>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="af3">Pediatrics, University of Iowa, Iowa City</nlm:aff>
<orgName type="university">Université de l'Iowa</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Iowa City</settlement>
<region type="state">Iowa</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name>
<affiliation wicri:level="1"><nlm:aff id="af4">Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University</wicri:regionArea>
<wicri:noRegion>Fudan University</wicri:noRegion>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="af5">Lindsley F. Kimball Research Institute, New York Blood Center, New York</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État de New York</region>
</placeName>
<wicri:cityArea>Lindsley F. Kimball Research Institute, New York Blood Center</wicri:cityArea>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Infectious Diseases</title>
<idno type="ISSN">0022-1899</idno>
<idno type="eISSN">1537-6613</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><title>Abstract</title>
<p>To gain entry into the target cell, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) uses its spike (S) protein S2 subunit to fuse with the plasma or endosomal membrane. Previous work identified a peptide derived from the heptad repeat (HR) 2 domain in S2 subunit, HR2P, which potently blocked MERS-CoV S protein–mediated membrane fusion. Here, we tested an HR2P analogue with improved pharmaceutical property, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo. HR2P-M2 was highly effective in inhibiting MERS-CoV S protein–mediated cell-cell fusion and infection by pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region. It interacted with the HR1 peptide to form stable α-helical complex and blocked six-helix bundle formation between the HR1 and HR2 domains in the viral S protein. Intranasally administered HR2P-M2 effectively protected adenovirus serotype-5–human dipeptidyl peptidase 4–transduced mice from infection by MERS-CoV strains with or without mutations in the HR1 region of S protein, with >1000-fold reduction of viral titers in lung, and the protection was enhanced by combining HR2P-M2 with interferon β. These results indicate that this combination regimen merits further development to prevent MERS in high-risk populations, including healthcare workers and patient family members, and to treat MERS-CoV–infected patients.</p>
</div>
</front>
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<author><name sortKey="Channappanavar, Rudragouda" sort="Channappanavar, Rudragouda" uniqKey="Channappanavar R" first="Rudragouda" last="Channappanavar">Rudragouda Channappanavar</name>
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<author><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name>
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<country xml:lang="fr">République populaire de Chine</country>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University</wicri:regionArea>
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<series><title level="j">The Journal of infectious diseases</title>
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<term>Coronavirus Infections (prevention & control)</term>
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<term>Lung (virology)</term>
<term>Mice, Inbred C57BL</term>
<term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term>
<term>Middle East Respiratory Syndrome Coronavirus (physiology)</term>
<term>Peptides (administration & dosage)</term>
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<term>Virus Internalization (drug effects)</term>
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<term>Animaux</term>
<term>Antiviraux (administration et posologie)</term>
<term>Charge virale</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie)</term>
<term>Humains</term>
<term>Infections à coronavirus ()</term>
<term>Lignée cellulaire</term>
<term>Modèles animaux de maladie humaine</term>
<term>Peptides (administration et posologie)</term>
<term>Poumon (virologie)</term>
<term>Pénétration virale ()</term>
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<term>Peptides</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term>
<term>Virus Internalization</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Coronavirus Infections</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Poumon</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Lung</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Administration, Intranasal</term>
<term>Animals</term>
<term>Cell Line</term>
<term>Disease Models, Animal</term>
<term>Humans</term>
<term>Mice, Inbred C57BL</term>
<term>Viral Load</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Administration par voie nasale</term>
<term>Animaux</term>
<term>Charge virale</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Humains</term>
<term>Infections à coronavirus</term>
<term>Lignée cellulaire</term>
<term>Modèles animaux de maladie humaine</term>
<term>Pénétration virale</term>
<term>Souris de lignée C57BL</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">To gain entry into the target cell, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) uses its spike (S) protein S2 subunit to fuse with the plasma or endosomal membrane. Previous work identified a peptide derived from the heptad repeat (HR) 2 domain in S2 subunit, HR2P, which potently blocked MERS-CoV S protein-mediated membrane fusion. Here, we tested an HR2P analogue with improved pharmaceutical property, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo. HR2P-M2 was highly effective in inhibiting MERS-CoV S protein-mediated cell-cell fusion and infection by pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region. It interacted with the HR1 peptide to form stable α-helical complex and blocked six-helix bundle formation between the HR1 and HR2 domains in the viral S protein. Intranasally administered HR2P-M2 effectively protected adenovirus serotype-5-human dipeptidyl peptidase 4-transduced mice from infection by MERS-CoV strains with or without mutations in the HR1 region of S protein, with >1000-fold reduction of viral titers in lung, and the protection was enhanced by combining HR2P-M2 with interferon β. These results indicate that this combination regimen merits further development to prevent MERS in high-risk populations, including healthcare workers and patient family members, and to treat MERS-CoV-infected patients. </div>
</front>
</TEI>
</pubmed>
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